Method of treating HIV-1 with α-substituted benzenemethanamine derivatives

ABSTRACT

The present invention is concerned with antiretroviral (e.g. anti HIV-1) compounds having the formula ##STR1## Pharmaceutical compositions containing said compounds of formula (I-a) or (I-b), and processes of preparing said compounds and compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 08/240,735, filedMay 12, 1994, now U.S. Pat. No. 5,407,961, which was based upon PCTApplication No. PCT/EP 92/02995, filed Dec. 22, 1992, which claimspriority from EPO application Ser. No. 91.203.430.3, filed Dec. 30,1991.

BACKGROUND OF THE INVENTION

In U.S. Pat. No. 4,246,429 there are described a number ofbenzeneacetamides and thioamides being useful as intermediates in thepreparation of phytopharmaceutical compounds. Unexpectedly, it has nowbeen found that some analogous intermediates effectively inhibit thereplication of HIV and consequently may be useful for the treatment ofindividuals infected by HIV, in particular HIV-1.

DESCRIPTION OF THE INVENTION

The present invention is concerned with compounds having the formula##STR2## the pharmaceutically acceptable acid addition salts thereof andthe stereochemically isomers forms thereof, wherein

R¹ is

trifluoromethyl; methylcarbonyl or C₃₋₆ cycloalkyl; or

a radical --C(═X)-NR¹⁶ R¹⁷, wherein X is O or S, and R¹⁶ and R¹⁷ eachindependently are hydrogen or C₁₋₄ alkyl; or

a radical --Alk--R¹⁸, wherein Alk is C₁₋₄ alkanediyl, and R¹⁸ ishydrogen or hydroxy;

R² and R³ each independently are halo or methyl;

R⁴ is hydrogen, hydroxy, halo, nitro, or trifluoromethyl;

R⁸ represents hydrogen, C₁₋₆ alkyloxy, C₁₋₆ alkyl, halo, nitro,aminocarbonyl, or a radical C₁₋₆ alkyl--(C═Z)--, wherein Z represents O,N--OH, N--OCH₃, N--NH₂ or N--N(CH₃)₂ ;

R⁷ represents hydrogen, in which case R⁵ and R⁶ taken together form abivalent radical of formula (CH₂)_(m) wherein m is 3 or 4,--(C═O)--O--CH₂ --, --(C═O)--O--(CH₂)₂ --, --(C═O)--(CH₂)₂ --,--(C═O)--(CH₂)₃ --, --(C═O)--CH₂ --O--, --(C--O)--CH₂ --NH--,--(C═O)--(CH₂)₂ --O--, --O--(CH₂)₂ --, --O--(CH₂)₃ --, --N═CH--CH═CH--,--(N-->O)═CH--CH═CH-- or --(C═O)--NH--CH═N--, wherein one or twohydrogen atoms can optionally be replaced with C₁₋₄ alkyl; or

R⁶ and R⁷ taken together form a bivalent radical of formula --(CH₂)_(m)-- wherein m is 3 or 4 and wherein one or two hydrogen atoms canoptionally be replaced with C₁₋₄ alkyl, in which case R⁵ representshydrogen, C₁₋₆ alkyloxy, C₁₋₆ alkyl, halo, nitro, aminocarbonyl, or aradical C₁₋₆ alkyl--(C═Z), wherein Z is as defined hereinabove;

R⁹ is

trifluoromethyl, methylcarbonyl or C₃₋₆ cycloalkyl; or

a radical --Alk--R¹⁹, wherein Alk is C₁₋₄ alkanediyl; and R¹⁹ ishydrogen or hydroxy;

R¹⁰ and R¹¹ each independently are halo or methyl;

R¹² is hydrogen, hydroxy, halo, nitro or trifluoromethyl;

R¹³ represents C₁₋₆ alkyloxy, nitro, trifluoromethoxy,2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl, aminocarbonyl,(cyclopropyl)carbonyl or a radical C₁₋₆ alkyl--C(═Z)-- wherein Z isdefined as hereinabove; and R¹⁴ and R¹⁵ each independently are hydrogen,halo, C₁₋₄ alkyl, nitro, C₁₋₄ alkyloxy or trifluoromethyl.

The compounds of formula (I) wherein at least one of R¹⁶ and R¹⁷ ishydrogen may also exist in their tautomeric form. Said form although notexplicitly indicated hereinabove is intended to be included within thescope of the present invention.

In the foregoing definitions halo defines fluoro, chloro, bromo andiodo; C₁₋₄ alkyl defines straight and branch chained saturatedhydrocarbon radicals having from 1 to 4 carbon atoms, such as, forexample, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, and 1,1-dimethylethyl; C₁₋₆ alkyl defines C₁₋₄ alkyl andthe higher homologs thereof having 5 or 6 carbon atoms, such as, forexample, pentyl, hexyl and the like; C₁₋₄ alkanediyl defines bivalentstraight or branch chained hydrocarbon radicals containing from 1 to 4atoms, such as, fox example, 1,2-ethanediyl, 1,3-propanediyl,1,4-butanediyl and the branched isomers thereof; C₃₋₆ cycloalkyl definescyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I-a) or (I-b) are able toform. Said salts can conveniently be obtained by treating the base formof the compounds of formula (I-a) or (I-b) with appropriate acids suchas inorganic acids, for example, hydrohalic acid, e.g. hydrochloric,hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids, such as, for example, acetic,hydroxyacetic, propanoic, 2-hydroxypropanoic, 2-oxo-propanoic,ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic,(E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propane-tricarboxylic, methanesulfonic, ethanesulfonic,benzene-sulfonic, 4-methylbenzene-sulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be convened by treatment with alkali intothe free base form. The term acid addition salt also comprises thehydrates and solvent addition/brms which the compounds of formula (I-a)or (I-b) are able to form. Examples of such forms are e.g. hydrates,alcoholales and the like.

The term "stereochemically isomeric forms" as used hereinbefore definesthe different isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers, and/or enantiomers of the basic molecular structure. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Interesting compounds are those compounds of formula (I-a), wherein R¹is a radical --C(═X)NR¹⁶ R¹⁷, wherein X is O or S, R¹⁶ and R¹⁷ eachindependently are hydrogen or C₁₋₄ alkyl; R² and R³ are halo; and R⁴ ishydrogen or halo.

More interesting compounds are those interesting compounds of formula(I-a), wherein R¹ represents a radical --CONH₂ ; R⁸ represents halo,C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl; and R⁷ represents hydrogen when R⁵ andR⁶ taken together form a bivalent radical of formula --(C═O)--O--CH₂ --,--(C--O)--O--(CH₂)₂ --, --(C═)--(CH₂)₂ --, --(C═O)≧(CH₂)₃ --,--(C═O)--CH₂ --O--, --(C═O)--(CH₂)₂ --O--, --O--(CH₂)₂ --, --O--(CH₂)₃--, or --(N→O)═CH--CH═CH--; or

R⁶ and R⁷ taken together form a bivalent radical of formula --(CH₂)_(m)-- wherein m represents 3 or 4 and R⁵ represents hydrogen or C₁₋₄alkylcarbonyl.

Particularly interesting compounds are those more interesting compoundsof formula (I-a) wherein R⁸ represents fluoro, chloro, bromo, methyl ormethylcarbonyl; and R⁷ represents hydrogen when R⁵ and R⁶ taken togetherform a bivalent radical of formula --(C═O)--O--CH₂, --(C═O)--(C₂)₂ --,--(C═O)--CH₂ --O--, --O--(CH₂)₂ --, or --(N→O)═CH--CH═CH--; or R⁶ and R⁷taken together form a bivalent radical of formula --(CH₂)₃ -- and R⁵represents hydrogen.

Preferred compounds of formula (I-a) are:

α-[(6-acetyl-2,3-dihydro-1H-inden-5-yl)amino]-2,6-dichlorobenzeneacetamide;

2,6-dichloro-α-[(5-chloro-2,3-dihydro-7-benzofuranyl)amino]benzeneacetamide;

2,6-dichloro-α-[(2,3-dihydro-6-methyl-3-oxo-1H-inden-4-yl)amino]benzeneacetamide;

2,6-dichloro-α-(8-quinolinylamino )benzeneacetamide-1-oxide;

2,6-dichloro-α-[(2,3-dihydro-3-oxo-4-benzofuranyl)amino]benzeneacetamide,the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof.

Other interesting compounds are those compounds of formula (I-b),wherein R⁹ is cyclopropyl or a radical --Alk--R¹⁹, R¹⁰ and R¹¹ are halo;and R¹² is hydrogen or halo.

More interesting compounds are those interesting compounds of formula(I-b), wherein R⁹ is cyclopropyl, methyl, ethyl or hydroxymethyl; R¹³represents C₁₋₄ alkyloxy, nitro or C₁₋₄ alkylcarbonyl; and R¹⁴ and R¹⁵each independently represent hydrogen or C₁₋₄ alkyl.

Particularly interesting compounds are those more interesting compoundsof formula (I-b), wherein R¹³ represents nitro or methylcarbonyl; andR¹⁴ and R¹⁵ represent hydrogen.

Preferred compounds of formula (I-b) are:

2,6-dichloro-a-methyl-N-(2-nitrophenyl)benzenemethanamine.

1-[2-[[1-(2,6-dichlorophenyl)ethyllamino]phenyl]ethanone;

2,6-dichloro-β-[(2-nitrophenyl)amino]benzeneethanol;

1-[2-[[1-(2,6-dichlorophenyl)propyl]amino]phenyl]ethanone;

1-[2-[[cyclopropyl(2,6-dichlorophenyl)methyl]amino]phenyl]ethanone;

the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof.

The compounds of formula (I-a) can generally be prepared by reacting anintermediate of formula (II-a) with an appropriate bicyclic derivativeof formula (III-a) ##STR3##

In formula (III-a) W¹ represents a reactive leaving group, such as, forexample, halo, C₁₋₆ alkyloxy, aryloxy, (C₁₋₆ alkyl or aryl)sulfonyloxy,(C₁₋₆ alkyl or aryl)sulfonyl, C₁₋₆ alkylthio or nitro, preferablyfluoro, bromo, chloro, nitro, 4-methylbenzenesulfonyloxy, methoxy ormethylthio.

The compounds of formula (1-b) can generally be prepared in an analogousway by reacting an intermediate of formula (II-b) with an appropriatebenzenederivative (III-b). ##STR4##

In formula (Ill-b) W¹ represents a leaving group as defined above. Theabove reactions can be performed by stirring the reactants, preferablyat an elevated temperature and in particular at the reflux temperatureof the reaction mixture, whereby an excess of one of the reactants canbe used as solvent; or optionally in admixture with an appropriatesolvent such as, for example, a dipolar aprotic solvent, e.g.N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,1-methyl-2-pyrrolidinone, acetonitrile; an ether, e.g. tetrahydrofuran,1,1'-oxybisethane, 1,4-dioxane and the like; and mixtures of suchsolvents.

An appropriate base such as, for example, an alkali metal or an earthalkaline metal carbonate, hydrogen carbonate, hydroxide, oxide,carboxylate, alkoxide, hydride or amide, e.g. sodium carbonate, sodiumhydrogen carbonate, potassium carbonate, sodium hydroxide, calciumoxide, sodium acetate, sodium methoxide and the like, or an organic basesuch as, for example, an amine, e.g. N,N-diethylethanamine,N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine,1,4-diazabicyclo[2.2.21octane, pyridine and the like, may optionally beused to pick up the acid which is formed during the course of thereaction. Additionally, it may be advantageous to conduct saidalkylation under an inert atmosphere such as, for example, oxygen-freeargon or nitrogen gas.

The compounds of formula (I-a) can also be prepared by alkylating anappropriate bicyclic derivative of formula (V-a) or a salt thereof, withan alkylating reagent of formula (IV-a) following art-known N-alkylationprocedures. In formula (IV-a) W² represents a reactive leaving groupsuch as, for example halo, e.g. chloro, bromo or iodo, asulfonyloxygroup, e.g. methanesulfonyloxy, trifluoromethanesulfonyloxy,benzenesulfonyloxy, 4-methylbenzenesulfonyloxy, naphthalenesulfonyloxyand the like reactive leaving groups. ##STR5##

Said N-alkylation reaction can conveniently be carried out by stirringthe reactants, optionally in a reaction-inert solvent such as, forexample, an aromatic solvent, e.g. benzene, methylbenzene,dimethylbenzene, chlorobenzene, methoxybenzene and the like; a ketone,e.g. 2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g.1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; a dipolaraprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide,dirnethylsulfoxide, pyridine, acetonitrile and the like; or a mixture ofsuch solvents.

An appropriate base such as, for example, an alkali metal or an earthalkaline metal carbonate, hydrogen carbonate, hydroxide, oxide,carboxylate, alkoxide, hydride or amide, e.g. sodium carbonate, sodiumhydrogen carbonate, potassium carbonate, sodium hydroxide, calciumoxide, sodium acetate, sodium methoxide and the like, or an organic basesuch as, for example, an amine, e.g. N,N-diethylethanamine,N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine,1,4-diazabicyclo[2.2.2]octane, pyridine and the like, may optionally beused to pick up the acid which is formed during the course of thereaction. Additionally, it may be advantageous to conduct saidalkylation under an inert atmosphere such as, for example, oxygen-freeargon or nitrogen gas.

In an efficient alternative for the foregoing N-alkylation reactions oneof the reactants is used as a solvent and the reaction is conducted byheating and stirring this reaction mixture at an elevated temperature.

The compounds of formula (I-b) can be prepared in a similar manner byreacting an intermediate of formula(V-b) or a salt thereof, with analkylating reagent (IV-b) wherein W² is as defined under formula (IV-a).##STR6##

The compounds of formula (I-a) wherein R¹ is a radical of formula--C(═X)NH², said compounds being represented by formula (I-a-1) when Xis O and by formula (I-a-2) when X is S, can be prepared by reacting anitrile of formula (VI-a), with a reagent H2X (VII), namely water orhydrogen sulfide, under appropriate conditions. ##STR7##

The hydrolysis of the nitrile of formula (VI-a) to the correspondingamide of formula (I-a-1 ), can easily be carried out following art-knownprocedures. Preferably said hydrolysis is carded out at room temperatureor low temperatures such as, for example, between 0° C. and roomtemperature, in a concentrated strong acid, e.g. concentrated sulfuricacid, hydrochloric acid, hydrobromic acid and the like, optionally inthe presence of a small amount of water; or by stirring the nitrile offormula (VI-a) in a carboxylic acid, e.g. formic acid and the like,while bubbling hydrochloric acid through the reaction mixture.

The nitrile (VI-a) can conveniently be converted into the thioamide(I-a-2) by reaction with hydrogen sulfide in an appropriate solvent,e.g. pyridine, a mono-, di- or trimethylated pyridine and the likesolvents, and in the presence of an appropriate base such as an amine,e.g. N,N-diethylethanamine, N-methylmorpholine,N-(1-methyl-ethyl)-2-propanamine and the like. This latter reaction canconveniently be conducted at room temperature and in some instances evenat lower temperatures such as, for example, between about 0° C. and roomtemperature. The thioamide compounds of formula (I-a-2) can convenientlybe converted into the corresponding amides of formula (I-a-1) byreaction with an oxidizing reagent such as, for example, hydrogenperoxide in water, optionally in admixture with an organic co-solvent.

The compounds of formula (I-a) wherein R¹ is a radical --C(═O)NR¹⁶ R¹⁷,R¹⁶ and R¹⁷ each independently being hydrogen or C₁₋₄ alkyl; saidcompounds being represented by formula (I-a-3) can be prepared byreacting an aminoacid or a derivative thereof of formula (VIII-a), withan appropriate amine (IX). ##STR8##

Said preparation of the amides of formula (I-a-3) can conveniently becarded out following art-known amidation and transamidation reactions.For example, said amides can be prepared by reacting an appropriatecarboxylic acid (L is OH) with an amine (IX) in the presence of areagent capable of promoting amidation reactions. Typical examples ofsuch reagents are for example, dicyclohexylcarbodiimide,2-chloro-1-methylpyridinium iodide, phosphorus pentoxide,1,1'-carbonylbis[1H-imidazole], 1,1'-sulfonyl-bis[1H-imidazole] and thelike reagents.

Alternatively, said carboxylic acids may be convened into a suitablereactive functional derivative thereof such as, for example, an acylhalide, symmetric or mixed anhydride, ester, amide, acyl azide and thelike derivatives, before reaction with the amine of formula (IX). Saidreactive functional derivatives may be prepared following art knownmethods, for example, by reacting the carboxylic acid with ahalogenating reagent such as, for example, thionyl chloride, phosphoroustrichloride, polyphosphorous acid, phosphoryl chloride, oxalyl chlorideand the like, or by reacting said carboxylic acid with an acyl halidesuch as acetyl chloride, ethyl chloroformate and the like.

The compounds of formula (I-a), wherein R¹ is C₃₋₆ cycloalkyl or C₁₋₄alkyl, said radicals being represented by R la and said compounds beingrepresented by formula (I-a-4), can be prepared by reacting anorganometallic reagent of formula (XI-a) wherein R^(1a) represents C₃₋₆cycloalkyl or C₁₋₄ alkyl, and M represents a metal group, such as, forexample, lithium, halomagnesium, copperlithium, with an imine of formula(X-a), following art-known methodologies. ##STR9## In an analogous waythe compounds of formula (I-b) wherein, R⁹ is C₃₋₆ cycloalkyl or C₁₋₄alkyl, said radicals being represented by R^(9a) and said compoundsbeing represented by formula (I-b-4), can be prepared by reacting anorganometallic reagent of formula (XI-b), wherein M represents a metalgroup, such as, for example, lithium, halomagnesium, copperlithium, withan imine of formula (X-b). It may be necessary in the above additionreactions to protect certain functional groups of certain substituentsin the imines of formula (X-a) and (X-b) prior to the addition reaction.##STR10##

The compounds of formula (I-a) or (I-b) wherein R⁵, R⁶, R⁷, R⁹ or R¹³represent C₁₋₆ alkyl--C(═Y), wherein Y represents O, can be prepared byhydrolysing the corresponding acetal or ketal.

The compounds of formula (I-a), respectively the compounds of formula(I-b) can be converted into one another following an-known functionalgroup transformation reactions. For example, the compounds wherein R⁵,R⁶, R⁷, R⁸ or R¹³ represent a radical C₁₋₆ alkyl--C(═Z)-- wherein Zrepresents N--OH, N--OCH₃, N--NH₂ or N--N(CH₃)₂, can be preparedfollowing art-known procedures from the corresponding compounds whereinZ represents O by reaction with hydroxylamine, O-methyl-hydroxylamine,hydrazine or di(methyl)hydrazine or a suitable addition salt formthereof.

The carbonyl group of the compounds of formula (I-a) wherein R⁵ and R⁶taken together form a bivalent radical --C(═O)(CH₂)₂, --C(═O)(CH₂)₃,--C(═O)(CH₂)₂ --O, --C(═O)CH₂ --O-- or --C(═O)(CH₂)₂ --NH--, can beconvened into a methylene group following art-known reduction proceduressuch as, for example, by reaction with zinc-amalgam in an acid such ashydrochloric acid.

The compounds of this invention have at least one asymmetric carbon atomin their structure, namely the carbon atom bearing the R¹ respectivelythe R⁹ group. Said chiral center and any other chiral center which maybe present, can be indicated by the stereochemical descriptors R and S.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of an-known procedures. Diastereoisomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g. counter current distribution,liquid chromatography and the like. Pure stereochemically isomeric formsmay also be derived from the corresponding pure stereochemicallyisomeric forms of the appropriate starting materials, provided that thereactions occur stereospecifically. Preferably, if a specificstereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials. Stereochemicallyisomeric forms of the compounds of formula (I) are obviously intended tobe included within the scope of the invention.

The compounds of formula (I) as prepared in the above describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following an-known resolution procedures. Theracemic compounds of formula (I) which are sufficiently basic may beconverted into the corresponding diastereomeric salt forms by reactionwith a suitable chiral acid. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkalineor acidic hydrolysis.

An interesting manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography using a chiralstationary phase such as suitably derivatized cellulose, for example,tri(dimethylcarbamoyl)cellulose (Chiracel OD®) and similar chiralstationary phases.

As an alternative to the above-mentioned resolution of the compounds offormula (I), there should be mentioned also the resolution of racemicintermediates. Particularly useful intermediates for this purpose arethe aminoacid derivatives of formula (VIII-a) wherein L is hydroxy, saidintermediates being represented by formula (VIII-a-1). ##STR11##

The aminoacids of formula (VIII-a-1 ) can conveniently be resolved byformation of the corresponding diastereomefic salt forms by reactionwith a suitable chiral base such as phenylethanamine,naphthylethanamine, cinchonine and other alkaloid bases. Obviously, saidaminoacids may also be resolved by liquid chromatography using anappropriate chiral stationary phase.

The enantiomefic forms of the aminoacids of formula (VIII-a-1) areconverted into the enantiomeric forms of the compounds of formula (I-a)according to the procedures described hereinbefore for converting theintermediates of formula (VIII-a) into the compounds of formula (I-a).

A number of the intermediates and starting materials employed in theforegoing preparations are known compounds which can be preparedaccording to art-known methodologies of preparing said or similarcompounds. Some intermediates are less common or are novel, and a numberof preparation methods will therefore be described hereinafter in moredetail.

The intermediates of formula (VI-a), can be prepared by reacting anappropriate benzaldehyde (XII-a) with a bicyclic amino intermediate offormula (V-a) in the presence of a cyanide salt and a suitable solvent.##STR12##

As examples of cyanide salts there may be mentioned alkali metal andearth alkaline metal cyanides, e.g., sodium and potassium cyanide.Suitable solvents comprise, for example, water; alkanols, e.g. methanol,ethanol and the like, carboxylic acids, e.g. acetic acid, particularlyglacial acetic acid, propanoic acid and the like; or a mixture of suchsolvents. Said reaction is conveniently carded out by stirring at roomtemperature and, if desired, slightly heating the reactants, for examplebetween 40° C. and 60° C., in particular at about 50° C. In someinstances it is advantageous to carry out said reaction in the presenceof a metal salt such as, for example, anhydrous zinc chloride and thelike, in a non-aqueous solvent, particularly glacial acetic acid, asdescribed in Chem. Ber., 98, 3902 (1965).

Alternatively, an intermediate imine of formula (X-a) formed by reactingan aldehyde of formula (XI-a) with an amine of formula (V-a) followingart-known procedures, is reacted with trimethylsilylcyanide, in anappropriate solvent such as, for example, a halogenated hydrocarbon,e.g. trichloromethane in the presence of a suitable Lewis acid catalyst,e.g. zinc iodide. ##STR13##

The aniline derivatives of formula (V-a) wherein R⁵ and R⁶ are takentogether to form a bivalent radical of formula, --(C═O)--(CH₂)₂,--(C═O)--(CH₂)₃ --, --(C═O)CH₂ --O--, (C═O)CH₂ --NH--, --(C═O)--(CH₂)₂--O--, said radicals being represented by --(C═O)--T-- and saidderivatives being represented by formula (V-a-1), can be prepared bycyclizing an intermediate of formula (XIII) wherein R²¹ is C₁₋₄ alkyl,preferably methyl or ethyl, and wherein L is hydroxy, halo oralkylcarbonyloxy, with formation of intermediate (XIV) and subsequentdeprotection. ##STR14##

Said cyclization can be performed by reacting the amides of formula(XIII), wherein L is halo or alkylcarbonyloxy, with a Lewis acid andsuch as, for example aluminum chloride, ferric chloride, zinc chlorideand the like in a reaction-inert solvent such as carbondisulfide and thelike, or by reacting the amides of formula (XIII), wherein L is OH, withan acid such as for example polyphosphoric acid, sulfuric acid and thelike. Said deprotection can be performed following art-known proceduresto hydrolyze amides and may ensue during aqueous work-up of the reactionmixture.

The aniline derivatives of formula (V-a) and (V-b) can be prepared byreducing nitrobenzene derivatives following art-known procedures.

Acylation of said aniline derivatives can be performed by reacting aprotected aniline derivative, preferably as an amid, with acylatingreagent, such as for example, an acid, e.g. acetic acid, propanoic acid,butanoic acid in the presence of polyphosphoric acid, sulfuric acid andthe like; or an acid derivative such as an acyl halide or an acidanhydride and the like in the presence of a Lewis acid such as aluminumchloride, ferric chloride and the like. An interesting alternative forsaid acylation is reacting a benzene derivative with a nitrile in thepresence of a Lewis acid such as for example boron trichloride andsubsequent hydrolysis of the intermediate imine.

The compounds of formula (I) show antiretroviral properties, inparticular against Human Immunodeficiency Virus (HIV), also known asLAV, HTLV-III or ARV, which is the etiological agent of Acquired ImmuneDeficiency Syndrome (AIDS) in humans. The HIV virus preferentiallyinfects human T-4 cells and destroys them or changes their normalfunction, particularly the coordination of the immune system. As aresult, an infected patient has an everdecreasing number of T-4 cells,which moreover behave abnormally. Hence, the immunological defensesystem is unable to combat infections and neoplasms and the HIV infectedsubject usually dies by opportunistic infections such as pneumonia, orby cancers. Other conditions associated with HIV infection includethrombocytopaenia, Kaposi's sarcoma and infection of the central nervoussystem characterized by progressive demyelination, resulting in dementiaand symptoms such as, progressive dysarthria, ataxia and disorientation.HIV infection further has also been associated with peripheralneuropathy, progressive generalized lymphadenopathy (PGL) andAIDS-related complex (ARC).

Due to their antiretroviral properties, particularly their anti-HIV andespecially their anti-HIV-1 properties, the compounds of formula (I),their pharmaceutically acceptable salts and the stereochemicallyisomeric forms thereof, are useful in the treatment of individualsinfected by HIV and for the prophylaxis of individuals. In general, thecompounds of the present invention may be useful in the treatment ofwarm-blooded animals infected with viruses whose existence is mediatedby, or depends upon, the enzyme reverse transcriptase. Conditions whichmay be prevented or treated with the compounds of the present invention,especially conditions associated with HIV and other pathogenicretroviruses, include AIDS, AIDS-related complex (ARC), progressivegeneralized lymphadenopathy (PGL), as well as chronic CNS diseasescaused by retroviruses, such as, for example HIV mediated dementia andmultiple sclerosis.

Additionally, it has been found that also the intermediates of formula(VI-a) show antiretroviral properties, in particular against HIV andespecially against HIV-1.

The subject compounds may be formulated into various pharmaceuticalforms for administration purposes. As appropriate compositions there maybe cited all compositions usually employed for systemically or topicallyadministering drugs. To prepare the pharmaceutical compositions of thisinvention, an effective amount of the particular compound, optionally inacid-addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carder, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable,particularly, for administration orally, rectally, percutaneously, or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represents the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large pan, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are-intendedto be convened, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. As appropriate compositions for topicalapplication them may be cited all compositions usually employed fortopically administering drugs, e.g., creams, gellies, dressings,shampoos, tinctures, pastes, ointments, salves, powders and the like.Application of said compositions may be by aerosol e.g. with apropellent such as nitrogen, carbon dioxide, a freon, or without apropellent such as a pump spray, drops, lotions, or a semisolid such asa thickened composition which can be applied by a swab. In particularcompositions, semisolid compositions such as salves, creams, gellies,ointments and the like will conveniently be used.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such dosage unit forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, injectable solutions or suspensions and the like, andsegregated multiples thereof.

Those of skill in the treatment of HIV-infection could easily determinethe effective daily amount from the test results presented here. Ingeneral it is contemplated that an effective daily amount would be from0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

It is evident that said effective daily amount may be lowered orincreased depending on the response of the treated subject and/ordepending on the evaluation of the physician prescribing the compoundsof the instant invention. The effective daily amount ranges mentionedhereinabove are therefore guidelines only and are not intended to limitthe scope or use of the invention to any extent.

The following examples are intended to illustrate and not to limit thescope of the present invention.

EXPERIMENTAL PART A. Preparation of the Intermediates Example 1

a) To a stirred mixture of 10.5 g of N-(2,3-dihydro-1H-inden-5-yl)acetamide and 4.7 ml of acetyl chloride in 100 ml ofcarbondisulfide were added portionwise 17.3 g of aluminum chloride atroom temperature. After stirring for 2 hours at reflux temperature, thecooled reaction mixture was poured into 50 ml ice/HCl. The separatedaqueous layer was extracted with dichloromethane. The extract wascombined with the former organic layer, washed with water, dried,filtered and evaporated. The residue was purified by columnchromatography (silica gel; dichloromethane/methanol 99:1 ). The eluentof the desired fraction was evaporated and the residue was crystallizedfrom 2,2'-oxybispropane. The crystallized product was filtered off anddried, yielding 6.3 g (48.3%) of N-(6-acetyl-2,3-dihydro-1H-inden-5-yl)acetamide (interm. 1).

b) A solution of 6.3 g of intermediate (1) in 75 ml of a hydrochloricacid solution 5N was refluxed for 45 minutes. After cooling, thereaction mixture was treated with ammonia. The precipitated product wasfiltered off, washed with water and dissolved in dichloromethane. Afterwashing with water, the separated organic layer was dried, filtered andevaporated, yielding 4.2 g (82.7%) of1-(6-amino-2,3-dihydro-1H-inden-5-yl)ethanone (interm. 2 ).

Example 2

a) To a stirred and cooled mixture of 32 ml of sulfuric acid and 14 mlof water there were added 17 g of 2,3-dihydro-5-chlorobenzofuran, whilekeeping the temperature at 25° C. After cooling to 0° C. there wereadded dropwise 14 ml of nitric acid. Stirring and cooling at 0° C. wascontinued for 44 hours. The reaction mixture was diluted with water(temp. <10° C.) and stirred for 15 min. The precipitate was filteredoff, washed with water and recrystallized from a mixture of ethylacetate and hexane (30:70), yielding 8.9 g (40.5%) of5-chloro-2,3-dihydro-7-nitrobenzofuran (interm. 3).

b) A mixture of 4.0 g of intermediate (3), 1 ml of a solution ofthiophene in methanol 4%, and 150 ml of methanol was hydrogenated for 2hours at normal pressure and room temperature in the presence of 2 g ofplatinum-on-charcoal catalyst 5%. The catalyst was filtered off overdiatomaceous earth and washed with methanol. The combined filtrates wereevaporated and the residue was purified by column chromatography (silicagel; ethyl acetate/n.hexane 15:85). The eluent of the desired fractionwas evaporated, yielding 2.7 g (79.6%) of5-chloro-2,3-dihydro-7-benzofuranamine (interm. 4).

Example 3

a) A mixture of 129 g of 2-chloro-1,3-dimethyl-5-nitrobenzene, 125 g of1-bromo-2,5-pyrrolidinedione, 12 g of dibenzoyl peroxide and 1200 ml oftetrachloromethane was stirred for 2 hours at reflux temperature using awater separator. Twice there was added an extra portion of 20 g ofdibenzoyl peroxide during a refluxing period of 29 hours. After cooling,the reaction mixture was washed with water, dried, filtered andevaporated. The residue was purified by column chromatography (silicagel; CH₂ Cl₂ /hexane 50:50). The eluent of the desired fraction wasevaporated, yielding 130 g (70.2%) of1-(bromomethyl)-2-chloro-3-methyl-5-nitrobenzene (interm. 5).

b) To a solution of 116 g of triethyl methanetricarboxylate in 750 ml ofN,N-dimethylformamide there were added portionwise 24 g of sodiumhydride under a nitrogen atmosphere. After stirring for 1 hour at roomtemperature, there was added dropwise a solution of 130 g ofintermediate (9) in 300 ml of N,N-dimethylformamide. Stirring at roomtemperature was continued overnight. The reaction mixture was evaporatedand the residue was partitioned between water and dichloromethane. Theaqueous layer was separated and re-extracted with dichloromethane (2x).The combined organic layers were washed with 5% Na₂ CO₃ (aq.) and water,dried, filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /hexane 80:20). The eluent of thedesired fraction was evaporated, yielding 102 g (49.1%) of triethyl2-(2-chloro-3-methyl-5-nitrophenyl)-1,1,1-ethanetricarboxylate (interm.6).

c) A mixture of 102 g of intermediate (6), 1000 ml of acetic acid and1000 ml of sulfuric acid was stirred for 3 hours at reflux temperature.After cooling, the reaction mixture was poured into ice-water and thewhole was stirred for 1 hour. The precipitate was filtered off (*),recrystallized from 2,2'-oxybispropane and dried in vacuo at 70° C.,yielding 28 g (46.9%) of product. The aqueous layer of the flitrate(*)was extracted with dichloromethane (2x). The combined extracts weredried, filtered and evaporated and the residue was dissolved in2,2'-oxybispropane. This solution was extracted with NaOH 5% and theextract was acidified with HCl. The precipitate was filtered off anddried in vacuo at 70° C., yielding an additional 16 g (26.8%) ofproduct. Total yield: 44 g (73.7 % ) of2-chloro-3-methyl-5-nitrobenzenepropanoic acid (interm. 7).

d) A mixture of 28 g of intermediate (7), 400 ml of acetic acid, 5 ml ofa solution of thiophene in methanol 4 % and 50 ml of acetic anhydridewas hydrogenated at normal pressure and room temperature in the presenceof 5 g of platinum-on-charcoal catalyst 10%. After the calculated amountof hydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was co-evaporated with methylbenzene (2x),yielding 28 g (95.2%) of5-(acetylamino)-2-chloro-3-methylbenzenepropanoic acid (interm. 8).

e) A mixture of 28 g of intermediate (8) and 200 g of polyphosphoricacid was stirred for 1/2 hour at 120° C. The warm reaction mixture waspoured into water. The precipitate was filtered off and dissolved in amixture of dichloromethane and methanol. This solution was washed withwater, dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 99:1 ). The eluent ofthe desired fraction was evaporated, yielding 6.7 g (24.5%) ofN-(7-chloro-2,3-dihydro-6-methyl-3-oxo-1H-inden-4-yl)acetamide (interm.9).

f) A mixture of 7.6 g of intermediate (9), 2 ml of a solution ofthiophene in methanol 4%, 8 g of calciumoxide, 250 ml of methanol and250 ml of tetrahydrofuran was hydrogenated at normal pressure and 50° C.in the presence of 4 g of palladium-on-charcoal catalyst 10%. After thecalculated amount of hydrogen was taken up, the catalyst was filteredoff and the filtrate was evaporated. The residue was successivelycrystallized from 2,2'-oxybispropane and from acetonitrile. The productwas filtered off and dried in vacuo at 70° C. yielding 3 g (46.1% ) ofproduct. Evaporation of the mother liquors yielded an additional 2.6 g(40.0%) N-(2,3-dihydro-6-methyl-3-oxo-1H-inden-4-yl)acetamide (interm.10).

g) A mixture of 3 g of intermediate (10) and 50 ml of HC15N was stirredfor 1 hour at reflux temperature. After cooling, the reaction mixturewas basified with ammonia. The product was extracted withdichloromethane (2x) and the combined extracts were dried, filtered andevaporated, yielding 1.2 g (49.6%) of7-amino-2,3-dihydro-5-methyl-1H-inden-1-one (interm. 11 ).

Example 4

a) 1,2-dichloroethane (70ml) was stirred and cooled to 0°-5° C. undernitrogen flow. Boron trichloride (0.06 tool) was allowed to bubblethrough 1,2-dichloroethane for 30 minutes. A solution of2-chloro-5-methoxybenzenamine (0.055 mol) in 1,2-dichloroethane (20 ml)was added dropwise at <5° C. The reaction mixture was stirred for 15minutes at <15° C. (suspension). 2-chloroacetonitrile (0.13 tool) wasadded dropwise at <5° C. The resulting mixture was added dropwise to asolution of aluminium chloride (0.06 tool) in 1,2-dichloroethane (20ml), which was stirred at 5° C. Upon complete addition at 5°-10° C., thereaction mixture was stirred for 30 minutes at room temperature. Then,the reaction mixture was stirred and refluxed for 3 hours. The reactionmixture was cooled. HC12N (220 ml) was added dropwise, while the mixturewas cooled on an ice bath (temperature rise to 30° C., precipitationoccurred). Water (50 ml) and 1,2-dichloroethane (20 ml) were added. Thereaction mixture was warmed to 80° C. and stirred at this temperaturefor 30 minutes. The organic layer was separated. The aqueous layer wasextracted with 1,2-dichloroethane (2×50 ml). The organic layer wasseparated, combined with the previous organic phase, washed with water,dried (MgSO₄), filtered and the solvent was evaporated. The residue wassuspended in hexane, filtered off and dried (vacuum; 60° C.), yielding11.6 g 1-(2-amino-3-chloro-6-methoxyphenyl)-2-chloroethanone (90% impureproduct). A sample (3 g) was recrystallized from 2,2'-oxybispropane. Thecrystals were filtered off and dried (vacuum; 60° C.), yielding 1.6 g(48%) of 1-(2-amino-3-chloro-6-methoxyphenyl)-2-chloroethano mp. 111.9°C. (interm. 12).

b) Aluminium chloride (0.82 tool) was suspended in CH₂ Cl₂ (425 ml).Intermediate (12) (0.27 mol) in CH₂ Cl₂ (500 ml) was added dropwise(temperature raised till 30° C.) and the mixture was stirred andrefluxed for 6 hours. The mixture was cooled, decomposed with HC12N (11)and CH₂ Cl₂ and CH₃ OH were added. The organic layer was separated andthe aqueous layer was extracted with CH₂ Cl₂. The combined organiclayers were dried (MgSO₄), filtered off and evaporated. The residue waspurified by column chromatography over silica gel (eluent: hexane/ethylacetate 50/50). The pure fractions were collected and evaporated,yielding 20 g of fraction 1 and 10 g fraction 2 (total: 60%). A sample(10g) from fraction 1 was boiled up in CH₃ OH and N,N-diethylethanaminewas added. The mixture was cooled to 0° C. and filtered off. Theprecipitate was crystallized from CH₃ OH, cooled to 0° C., filtered offand dried in vacuo at 40° C., yielding 7.4 g (44.8%)4-amino-5-chloro-3(2H)-benzofuranone; mp. 160.0° C. (interm. 13 ).

c) A mixture of intermediate (13) (0.087 mol) and potassium acetate (10g) in methanol (250 ml) was hydrogenareal at 50° C. withpalladium-on-charcoal (5 g) as a catalyst in the presence of thiophene(0.5 ml). After uptake of hydrogen (1 equiv), the catalyst was filteredoff and the tiltrate was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂). The pure fractionswere collected and the solvent was evaporated, yielding 8.4 g (65%) of4-amino-3(2H)-benzofuranone (interm. 14).

d) A mixture of intermediate (14) (0.01 mol) and2,6-dichloro-benzaldehyde (0.01 mol) in methylbenzene (100 ml) wasstirred and refluxed for 20 hours, using a water-separator. The reactionmixture was cooled and the solvent was evaporated. The residue wasstirred in boiling 2,2'-oxybixpropane, cooled and the resultingprecipitate was filtered off, stirred in boiling 2-propanol, cooled,filtered off and dried (vacuum; 70° C.), yielding 1.8 g (60%) ofproduct. A sample (1g) was stirred in boiling CH₃ CN, filtered whilestill warm and dried (vacuum; 70° C.), yielding 0.5 g (29.4%) of4-[[(2,6-dichlorophenyl)methylene]amino]-3(2H)-benzofuranone (interm.15). In a similar manner was also prepared:7-[[(2,6-dichlorophenyl)methylenelamino]- 1 (3H)-isobenzofuranone(interm. 16).

Example 5

A solution of 3.5 g of intermediate (2) and 4.72 g of2,6-dichlorobenzaldehyde in 100 ml of acetic acid was stirred for 2hours at room temperature. 1.75 g of potassium cyanide was added andafter stirring for 20 hours at room temperature, the reaction mixturewas poured into water. The precipitated product was filtered off, washedwith water and recrystallized from 2-propanol. The product was filteredoff and dried, yielding 6 g (83.5%) of(±)-α-[(6-acetyl-2,3-dihydro-1H-inden-5-yl)amino]-2,6-dichlorobenzeneacetonitrile(interm. 17).

Example 6

A mixture of 15.3 g of 2,6-dichlorobenzaldehyde, 10 g of8-quinolinamine, 175 ml of acetic acid and 16.7 g of zinc(II)chloridewas stirred for 1 hour at room temperature. There were added 7 g ofpotassium cyanide and stirring at room temperature was continued for 4hours. The precipitate was filtered off* and dissolved indichloromethane. Unsoluble product was filtered off* and stirred for 24hours at 60° C. in 300 ml of acetic acid together with 7 g of potassiumcyanide. A first product fraction of 4.6 g (20.2%) was obtained. Thefiltrate* was washed with water, dried, filtered and evaporated. Theresidue was successively triturated in 2,2'-oxybispropane andrecrystallized from acetonitrile, yielding an additional productfraction of 0.9 g (3.9%). Total yield: 5.5 g (24.1%) of2,6-dichloro-α-(8-quinolinylamino) benzeneacetonitrile; mp. 160.6° C.(interm. 18).

Example 7

A mixture of intermediate (15) (0.0043 tool),trimethylsilanecarbonitrile (0.065 mol) and zinc iodide (catalyticamount) in trichloromethane (20 ml) was stirred for 20 hours at roomtemperature. Extra trimethylsilanecarbonitfile (1.1 ml) was added. Extrazinc iodide (catalytic amount) was added. The reaction mixture wasstirred at room temperature for the week-end. The reaction mixture waspoured out into water. The layers were separated. The aqueous layer wasextracted with CH₂ Cl₂. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ /hexane 7/3). Twodesired fractions were collected and the solvent was evaporated. Thefirst column fraction (0.3 g) was stirred in boiling 2,2'-oxybispropane,filtered off and dried (vacuum; 70° C.), yielding 0.25 g (18%) of(±)-2,6-dichloro-α-[(2,3-dihydro-3-oxo-4-benzofuranyl)amino]benzeneacetonitrile.

The following intermediates of formula (VI-a) were prepared:

    ______________________________________                                         ##STR15##                                                                     ##STR16##                                                                             ##STR17##                                                                              ##STR18##                                                                                      ##STR19##                                  ______________________________________                                        17      5                                                                                       ##STR20##       --                                          18      6                                                                                       ##STR21##       mp. 160.6° C.                        19      7                                                                                       ##STR22##       mp. 161.9° C.                        20      6                                                                                       ##STR23##       --                                          21      5                                                                                       ##STR24##       mp. 79.5° C.                         22      5                                                                                       ##STR25##       --                                          23      5                                                                                       ##STR26##       mp. 133.0° C.                        24      5                                                                                       ##STR27##       mp. 184.0° C.                        25      5                                                                                       ##STR28##       mp. 256.3° C.                        26      6                                                                                       ##STR29##       mp. 208.4° C.                        ______________________________________                                    

Example 8

a) 2-methyl-2-(2-nitrophenyl)- 1,3-dioxolane (0.132 mol) was dissolvedin tetrahydrofuran (600 ml) and this solution was hydrogenated withplatinum on activated carbon (4 g) as a catalyst in the presence ofcalcium oxide (10 g) and thiophene (3 ml). After uptake of H₂ (3 equiv),the catalyst was filtered on celite and washed with tetrahydrofuran. Theflitrate was evaporated. The residue was recrystallized from n-hexane.The crystals were filtered off and dried, yielding 18.5g (78%) of2-(2-methyl-1,3-dioxolan-2-yl)benzenamine (interm. 27).

b) A solution of 2,6-dichlorobenzaldehyde (0.028 mol) and intermediate(27) (0.028mol) in methylbenzene (100 ml) was stirred and refluxed for24 hours, using a Dean-Stark water separator. The solvent wasevaporated. The residue crystallized upon standing. The crystals werefiltered off and dried, yieldingN-[(2,6-dichlorophenyl)-methylene]-2-(2-methyl-1,3-dioxolan-2-yl)benzenamine(interm. 28).

c) Reaction performed under N₂ flow. A solution of bromocyclopropane(0.064 mol) in 1,1'-oxybisethane (48 ml) was added dropwise to asuspension of lithium (0.12 mol) in 1,1'-oxybisethane (48 ml;dry),stirred at 0° C. The reaction mixture was stirred for 90 minutes at4°-5° C. (ice-bath). A solution of intermediate (28) (0.048mol) in1,1'-oxybisethane (48 ml) was added (exothermic temperature rise). Thereaction mixture was stirred for 3 hours at room temperature. Thereaction mixture was cooled. Water was added. The organic layer wasseparated. The aqueous layer was extracted with CH₂ Cl₂. The organiclayer was separated, combined with previous organic phase, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified twice by column chromatography over silica gel (eluent: CH₂ Cl₂/hexane 50/50). The pure fractions were collected and the solvent wasevaporated. The residue was triturated in 2,2'-oxybispropane. The solidwas filtered off and dried, yielding 4.8g (26.5%) of(±)-2,6-dichloro-a-cyclopropyl-N-[2-(2-methyl-1,3-dioxolan-2-yl)phenyl]benzenemethanamine; mp. 150.7° C. (interm. 29).

B. Preparation of the Final Compounds Example 9

2.2 g of intermediate (23) was dissolved in 50 ml of formic acid. HC1was allowed to bubble through this solution for 15 min. The reactionmixture was stirred at room temperature for 1 hour. The reaction mixturewas poured out into water and the resulting precipitate was filteredoff, and crystallized for acetonitrile. The crystals were filtered offand dried in vacuo at 70° C., yielding 0.4 g (19%) of(±)-2,6-dichloro-α-[(2,3-dihydro-6-methyl-3-oxo-1H-inden-4-yl)amino]benzene-acetamide;m.p. 249.5° C. (comp. 1 ).

Example 10

Sodium hydroxide (2.5 ml) was added to a suspension of intermediate (19)(0.006 mol) in ethanol (60 ml). Hydrogen peroxide 30% (6ml) was addeddropwise at 0°-5° C. and the reaction mixture was stirred for 3 hours at60° C. The solvent was evaporated. The residue was partitioned betweenCH₂ Cl₂ and H₂ O. The layers were separated. The aqueous layer wasextracted twice with CHCl₃. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH 98/2). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from CH₃ CN. The crystals werefiltered off and recrystallized from CH₃ OH. The crystals were filteredoff and dried (vacuum; 80° C.), yielding 0.32 g (15%) of(±)-2,6-dichloro-α-[(2,3-di-hydro-3-oxo-4-benzofuranyl)amino]benzeneacetamide;mp. 245.4° C. (comp. 9)

Example 11

A mixture of 5.5 g of 1,3-dichloro-2-(1-bromoethyl)benzene and 2.9 g of2-(methylcarbonyl)benzeneamine was stirred for 8 hours at 100° C. Aftercooling, the reaction mixture was purified by column chromatography(silica gel; CH₂ Cl₂ /hexane 50:50). The eluent of the desired fractionwas evaporated and the residue was triturated in hexane. The product wasfiltered off and dried in vacuo at 60° C., yielding 1.05 g (16.2%) of(23-1-[2-[[1-(2,6-dichlorophenyl)ethyl]amino]phenyl]ethanone; mp. 122.8°C. (comp. 10).

Example 12

A mixture of 1.03 g of α-amino-2,6-dichlorobenzeneethanol and 0.7 g of1-fluoro-2-nitrobenzene was stirred for 3 hours at 110° C. The reactionmixture was purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃OH 98:2). The eluent of the desired fraction was evaporated and theresidue was crystallized from acetonitrile. The product was filtered offand dried, yielding 0.4 g (24.4%) of(±)-2,6-dichloro-β-[(2-nitrophenyl)amino]benzeneethanol; m.p. 127.6° C.(comp. 12).

Example 13

A mixture of intermediate (29) (0.0053 mol) in methanol (100 ml) andhydrochloric acid 6N (2 ml) was stirred for 2 hours at room temperature.The solvent was partially evaporated. The resulting precipitate wasfiltered off and recrystallized from CH₃ CN. The crystals were filteredoff and dried, yielding 1.1g (61.1%)(±)-1-[2-[[cyclopropyl-(2,6-dichlorophenyl)methyl]amino]phenyl]ethanone;m.p. 116.5° C. (comp. 14)

The following compounds of formula (I-a) were prepared:

    ______________________________________                                         ##STR30##                                                                     ##STR31##                                                                           ##STR32##                                                                              ##STR33##                                                                                       ##STR34##                                   ______________________________________                                        1     9                                                                                       ##STR35##        mp. 249.5° C.                         2     9                                                                                       ##STR36##        mp. 151° C.                           3     9                                                                                       ##STR37##        mp. 221.1° C.                         4     9                                                                                       ##STR38##        mp. 265.0° C.                         5     9                                                                                       ##STR39##        mp. 237.4° C.                         6     9                                                                                       ##STR40##        mp. 201.5° C.                         7     9                                                                                       ##STR41##        mp. 258.0° C.                         8     9                                                                                       ##STR42##        mp. 274.3° C.                         9     10                                                                                      ##STR43##        mp. 245.4° C.                         ______________________________________                                    

The following compounds of formula (I-b) were prepared:

    ______________________________________                                         ##STR44##                                                                     ##STR45##                                                                           ##STR46##                                                                             ##STR47##                                                                               ##STR48##                                                                                   ##STR49##                              ______________________________________                                        10    11      CH.sub.3                                                                                 ##STR50##    mp.  122.8° C.                   11    11      CH.sub.2 CH.sub.3                                                                        ##STR51##    mp. 100.7° C.                    12    12      CH.sub.2 OH                                                                              ##STR52##    mp. 127.6° C.                    13    12      CH.sub.3                                                                                 ##STR53##    mp. 141.8° C.                    14    13      cycloC.sub.3 H.sub.5                                                                     ##STR54##    mp. 116.5° C.                    ______________________________________                                    

C. Pharmacological Example Example 14

A rapid, sensitive and automated assay procedure was used for thein-vitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cellline, MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer,36, 445-451, 1985) to be highly susceptible to and permissive for HIVinfection, served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via thein-situ reduction of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The50% cytotoxic dose (CD₅₀ in μg/ml) was defined as the concentration ofcompound that reduced the absorbance of the mock-infected control sampleby 50%. The percent protection achieved by the compound in HIV-infectedcells was calculated by the following formula: ##EQU1## whereby(OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% effective dose (ED₅₀ in μg/ml). Theratio of CD₅₀ to ED₅₀ was defined as the selectivity index (SI).Particular values are listed in Table 1 hereinbelow.

                  TABLE 1                                                         ______________________________________                                        Co. No.  CD.sub.50 (μg/ml)                                                                       ED.sub.50 (μg/ml)                                                                     SI                                           ______________________________________                                         1       207           0.0038    54560                                         5       10           0.2        50                                            6       0.87         0.079      11                                            7       53           0.047      3255                                          9       168.7        0.12       1405                                         10       5            0.022      227                                          11       6.9          0.52       13                                           12       4.3          0.18       25                                           13       0.13         0.021       6                                           14       4.1          0.15       27                                           ______________________________________                                    

D. Composition examples

"Active ingredient (A.I.) as used throughout these examples relates to acompound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereochemically isomeric form thereof."

Example 15 :ORAL DROPS

500 Grams of the A.I. was dissolved in 0.5 1 of 2-hydroxypropanoic acidand 1.5 l of the polyethylene glycol at 60°˜80° C. After cooling to30°˜40° C. there were added 35 l of polyethylene glycol and the mixturewas stirred well. Then there was added a solution of 1750 grams ofsodium saccharin in 2.5 l of purified water and while stirring therewere added 2.5 l of cocoa flavor and polyethylene glycol q.s. to avolume of 50 l , providing an oral drop solution comprising 10 mg/ml ofA.I.. The resulting solution was filled into suitable containers.

Example 16 :ORAL SOLUTION

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 1 of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

Example 17:CAPSULES

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, comprising each 20 mg of the active ingredient.

Example 18: FILM-COATED TABLETS

Preparation of tablet core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 ml of water. The wet powder mixture was sieved, dried and sievedagain. Then there was added 100 grams microcrystalline cellulose and 15grams hydrogenated vegetable oil. The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each containing 10 mg ofthe active ingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml of denaturatedethanol there was added a solution of 5 grams of ethyl cellulose in 150ml of dichloromethane. Then there were added 75 ml of dichloromethaneand 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol wasmolten and dissolved in 75 ml of dichloromethane. The latter solutionwas added to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolour suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained mixture in a coating apparatus.

Example 19: INJECTABLE SOLUTION

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 1 of boiling water forinjection. After cooling to about 50° C. there were added while stiffing4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of theA.I.. The solution was cooled to room temperature and supplemented withwater for injection q.s. ad 1 l, giving a solution comprising 4 mg/ml ofA.I.. The solution was sterilized by filtration (U.S.P. XVII p. 811 )and filled in sterile containers.

Example 20: SUPPOSITORIES

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Gramssurfactant (SPAN®) and triglycerides (Witepsol 555 ®) q.s. ad 300 gramswere molten together. The latter mixture was mixed well with the formersolution. The thus obtained mixture was poured into moulds at atemperature of 37°-38° C. to form 100 suppositories each containing 30mg/ml of the A.I.

Example 21: INJECTABLE SOLUTION

60 Grams of A.I. and 12 grams of benzylalcohol were mixed well andsesame oil was added q.s. ad 1 l, giving a solution comprising 60 mg/mlof A.I. The solution was sterilized and filled in sterile containers.

Example 22:2% CREAM

75 mg Stearyl alcohol, 20 mg cetyl alcohol, 20 mg sorbitan monostearateand 10 mg isopropyl myristate are introduced into a doublewall jacketedvessel and heated until the mixture has completely molten. This mixtureis added to a separately prepared mixture of purified water, 200 mgpropylene glycol and 15 mg polysorbate 60 having a temperature of 70° to75° C. while using a homogenizer for liquids. The resulting emulsion isallowed to cool to below 25° C. while continuously mixing. A solution of20 mg of A.I. of formula (I), 1 mg polysorbate 80 and 637 mg purifiedwater and a solution of 2 mg sodium sulfite anhydrous in purified waterare next added to the emulsion while continuously mixing. The cream ishomogenized and filled into suitable tubes.

Example 23 :AEROSOLS

a) To a solution of 2.5 mg A.I. in 0.7 ml of distilled water there areadded 730 mg of a 0.1N hydrochloric acid solution. After stirring for 10minutes at room temperature, the pH of the thus obtained solution isadjusted to pH 5.5 by adding a 0.1N sodium hydroxide solution. Thenthere are added successively 4 mg of sodium chloride and 0.15 mg ofphenylmercuric acetate and the whole is stirred to produce a completesolution. Distilled water is then added to a volume of 1.0 ml. Thesolution is filled in a glass bottle closed with a mechanical pumpdelivering 0.1 ml per puff upon administration.

b) To a solution of 2 mg A.I. in 0.7 ml of distilled water there areadded 600 mg of a 0.1N hydrochloric acid solution. After stirring for 10minutes at room temperature, 10 mg of polyvinylalcohol is dissolved inthe mixture and the pH of the thus obtained solution is adjusted to pH5.5 by adding a 0.1N sodium hydroxide solution. Then there are addedsuccessively 4 m g of sodium chloride and 2 mg of phenylethyl alcoholand the whole is stirred to produce a complete solution. Distilled wateris added to produce a volume of 1.0 ml which is filled in a glass bottleclosed with a mechanical pump spray delivering 0.1 ml per puff uponadministration.

We claim:
 1. A method for treating individuals infected with HIV-1 whichcomprises administering to said individuals a pharmaceutically effectiveamount of a compound of the formula: ##STR55## a pharmaceuticallyacceptable acid addition salt or a stereochemically isomeric formthereof, wherein:R¹ istrifluoromethyl, methyl carbonyl or C₃₋₆cycloalkyl; or a radical --C(═X)--NR¹⁶ R¹⁷, wherein X is O or S, and R¹⁶and R¹⁷ each independently are hydrogen or C₁₋₄ alkyl; or a radical--Alk--R¹⁸, wherein Alk is C₁₋₄ alkanediyl, and R¹⁸ is hydrogen orhydroxy; R² and R³ each independently are halo or methyl; R⁴ ishydrogen, hydroxy, halo, nitro or trifluoromethyl; R⁸ representshydrogen, C₁₋₆ alkyloxy, C₁₋₆ alkyl, halo, nitro, aminocarbonyl, or aradical C₁₋₆ alkyl(C═Z)--, wherein Z represents ═O, ═N--OH, ═N--OCH₃,═N--NH₂ or ═N--N(CH₃)₂ ; R⁷ represents hydrogen, in which case R⁵ and R⁶taken together form a bivalent radical of formula --(CH₂)_(m) -- whereinm is 3 or 4, --(C═O)--O--CH₂ --, --(C═O)--O--(CH₂)₂ --, --(C═O)--(CH₂)₂--, --(C═O)--(CH₂)₃ --, --(C═O)CH₂ O--, --(C═O)CH₂ NH--, --(C═O)--(CH₂)₂--O--, --O--(CH₂)₂ --, --O--(CH₂)₃ --, --N═CH--CH═CH--,--(N→O)═CH--CH═CH-- or --(C═O)NH--CH═N--, wherein one or two hydrogenatoms can optionally be replaced with C₁₋ alkyl; or R⁶ and R⁷ takentogether form abivalent radical of formula --(CH₂)_(m) -- wherein m is 3or 4 and wherein one or two hydrogen atoms can optionally be replacedwith C₁₋₄ alkyl, in which case R⁵ represents hydrogen, C₁₋₆ alkyloxy,C₁₋₆ alkyl, halo, nitro, aminocarbonyl, or a radical C₁₋₆alkyl--(C═Z)--, wherein Z is as defined above; R⁹ istrifluoromethyl,methylcarbonyl or C₃₋₆ cycloalkyl; or a radical --Alk--R¹⁹, wherein Alkis C₁₋₄ alkanediyl and R¹⁹ is hydrogen or hydroxy; R¹⁰ and R¹¹ eachindependently are halo or methyl; R¹² is hydrogen, hydroxy, halo, nitroor trifluoromethyl; R¹³ represents C₁₋₆ alkyloxy, nitro,trifluoromethoxy, 2,2,2-trifluoroethoxy, (trifluoromethyl)carbonyl,aminocarbonyl, (cyclopropyl)carbonyl or a radical C₁₋₆ alkyl-(C═Z)--wherein Z is as defined hereinabove; and R¹⁴ and R¹⁵ each independentlyare hydrogen, halo, C₁₋₄ alkyl, nitro, C₁₋₄ alkyloxy or trifluoromethyl.2. The method of claim 1 wherein the compound is defined by Formula(I-a), and wherein R¹ is a radical --C(═X)NR¹⁶ R¹⁷, wherein X is O or S,R¹⁶ and R¹⁷ each independently are hydrogen or C₁₋₄ alkyl R² and R³ arehalo; and R⁴ is hydrogen or halo.
 3. The method of claim 2 wherein thecompoundis:α-[(6-acetyl-2,3-dihydro-1H-inden-5-yl)amino]-2,6-dichloro-benzeneacetamide;2,6-dichloro-α-[(5-chloro-2,3-dihydro-7-benzofuranyl)amino]-benzeneacetamide;2,6-dichloro-α-α(2,3-dihydro-6-methyl-3-oxo-1H-inden-4-yl)amino]-benzeneacetamide;2,6-dichloro-α-[(8-quinolinylamino)benzeneacetamide-1-oxide;2,6-dichloro-α-[(2,3-dihydro-3-oxo-4-benzofuranyl)amino]-benzeneacetamide;or a pharmaceutically acceptable acid addition salt or astereochemically isomeric form thereof.
 4. A method according to claim 1wherein the compound is defined by Formula (I-b) and wherein R⁹ iscyclopropyl or a radical --Alk--R¹⁹ ; wherein R¹⁰ and R¹¹ are halo; andwherein R¹² is hydrogen or halo.
 5. A method according to claim 4wherein the compound is:2,6 -dichloro-α-methyl-N- ( 2-nitrophenyl)benzenemethaneamine; 1-[2-[[1-(2,6-dichlorophenyl)ethyl]amino]phenyl]ethanone; 2.6-dichloro-α-[(2-nitrophenyl)amino]benzeneethanol;1-[2-[[1-(2,6-dichlorophenyl)propyl]amino]phenyl]ethanone;1-[2-[[cyclopropyl(2,6-dichlorophenyl)methyl]amino]-phenyl]ethanone; ora pharmaceutically acceptable acid addition salt or a stereochemicallyisomeric form thereof.